Quinoline or quinazoline derivatives, their production and use

ABSTRACT

A compound represented by the general formula: ##STR1## wherein Y represents a nitrogen atom or C--G (G represents a carboxyl group which may be esterified); ring R is a nitrogen-containing unsaturated heterocyclic group which may be substituted or unsubstituted; each of rings A and B may have a substituent; n represents an integer from 1 to 4; k represents the integer 0 or 1, or a salt thereof, which serves well as an anti-inflammatory agent, particularly a therapeutic agent for arthritis.

FIELD OF THE INVENTION

The present invention relates to a new quinoline or quinazolinederivative or a salt thereof which serves well as an anti-inflammatoryagent, particularly a therapeutic agent for arthritis. Additionally,these compouns and compositions can be used in the diagnosis of suchdisease states.

BACKGROUND OF THE INVENTION

Arthritis, an inflammatory disease of the joint, occurs in various formssuch as rheumatoid arthritis and related diseases with jointinflammation.

Rheumatoid arthritis, also called chronic rheumatism, in particular, isa chronic multiple arthritis characterized by inflammatory changes inthe synovial membrane of the articular capsule inner layer. Arthriticdiseases like rheumatoid arthritis are progressive and cause jointdisorders such as deformation and acampsia, often resulting in severephysical disorder due to lack of effective treatment and subsequentdeterioration.

Traditionally, these forms of arthritis have been chemotherapeuticallytreated with various agents, including steroids such as cortisone andother adrenocortical hormones, non-steroidal anti-inflammatory agentssuch as aspirin, piroxicam and indomethacin, gold agents such asaurothiomalate, antirheumatic agents such as chloroquine preparationsand D-penicillamine, anti-gout agents such as colchicine, andimmunosuppressors such as cyclophosphamide, azathioprine, methotrexateand levamisole.

However, these drugs have drawbacks such as severe adverse reactions,adverse reactions hampering the drug's long-term use, lack of sufficientefficacy and a failure to be effective against already-occurringarthritis.

Accordingly, there is need for the development of a drug which exhibitsexcellent prophylactic/therapeutic action on arthritis, with lowtoxicity in clinical situations.

Traditionally, various compounds have been synthesized as quinoline orquinazoline derivatives. Known compounds having an aminomethyl group atthe 2-position of a 4-phenylquinoline or 4-phenylquinazoline skeletoninclude the 2-dimethylaminomethyl derivative and 2-morpholinomethylderivative described in Synthesis, Vol. 9, p. 718 (1979), and the2-alkylaminomethylquinoline derivative described in the Farmaco, Vol.44, 555 (1989). However, there is no disclosure of any compound whereinthe 2-position of a 4-phenylquinoline or 4-phenylquinazoline skeleton isbound to a nitrogen atom of a nitrogen-containing unsaturatedheterocyclic ring via an alkylene group as in the present invention.

OBJECTS OF THE INVENTION

One object of the invention is to provide a novel quinoline orquinazoline derivatives useful as an anti-inflammatory agent.

Another object of the invention is to provide method for producting theabove quinoline or quinazoline derivatives.

Further, another object of the present invention is to provide a novelanti-inflammatory agent containing a quinoline or quinazolinederivative.

These object as well as other objects and advantages of the presentinvention will become apparent to those skilled in the art from thefollowing description.

SUMMARY OF THE INVENTION

The present inventors found that a compound wherein the 2-position of a4-phenylquinoline or 4-phenylquinazoline skeleton is bound to a nitrogenatom of a nitrogen-containing unsaturated heterocyclic ring via analkylene group exhibits anti-arthritic action and serves well as a jointdestruction suppressor. The inventors made investigations based on thisfinding, and developed the present invention.

Accordingly, the present invention relates to:

(1) a compound represented by general formula (I): ##STR2## wherein Yrepresents a nitrogen atom or C--G (G represents a carboxyl group whichmay be esterified); ring R is a nitrogen-containing unsaturatedheterocyclic group which may be substituted or unsubstituted; each ofrings A and B may have substituents; n represents an integer from 1 to4; k represents the integer 0 or 1, or a salt thereof;

(2) a method of producing a compound represented by general formula (I):##STR3## wherein Y represents a nitrogen atom or C--G (G represents acarboxyl group which may be esterified); rings A and B may havesubstituents; ring R represents a nitrogen-containing unsaturatedheterocyclic group which may be substituted or unsubstituted; nrepresents an integer from 1 to 4; k represents the integer 0 or 1, or asalt thereof; by reacting a compound represented by general formula(II): ##STR4## wherein Q represents a leaving group; the other symbolshave the same definitions as above, with a compound represented bygeneral formula (III): ##STR5## wherein ring R has the same definitionas above, and

(3) an anti-inflammatory agent containing a compound represented bygeneral formula (I): ##STR6## wherein Y represents a nitrogen atom orC--G (G represents a carboxyl group which may be esterified); ring R isa nitrogen-containing unsaturated heterocyclic group which may besubstituted or unsubstituted; each of rings A and B may havesubstituents; n represents an integer from 1 to 4; k represents theinteger 0 or 1, or a salt thereof.

The above general formulas and various definitions included in the scopeof the present invention are hereinafter described in detail withtypical examples thereof.

DETAILED DESCRIPTION OF THE INVENTION

With respect to general formulas (I) and (III), the nitrogen-containingunsaturated heterocyclic group for ring R, which may be substituted orunsubstituted, is exemplified by unsaturated heterocyclic ringscontaining 1 or more nitrogen atoms, preferably 1 to 4 nitrogen atoms asring component atoms. Preferable unsaturated heterocyclic groups include5-membered nitrogen-containing unsaturated heterocyclic groups such asimidazol-1-yl, pyrazol-1-yl, 1,2,4-triazol-1-yl, 1,2,4-triazol-4-yl,1,2,3-triazol-1-yl, 1,2,3-triazol-2-yl, pyrrol-1-yl and tetrazol-1-yl,2-pyrrolin-1-yl, 3-pyrrolin-1-yl, 2-imidazolin-1-yl, 2-pyrazolin-1-yl,3-pyrazolin-1-yl, each of which may form a condensed ring (e.g.,benzimidazol-1-yl, indol-1-yl, 1H-indazol-1-yl, benzotriazol-1-yl,benzotriazol-2-yl, isoindol-2-yl, 7-purinyl,1H-pyrrolo[1,2-b][1,2,4]triazol-1-yl, 1,8-dihydroimidazo[1,2-a]pyridin-1-yl, 1,8a-dihydro[1,2,4]triazolo[1,5a]pyridin-1-yl,3,3a-dihydro[1,2,4]triazolo[1,5 -a]pyrimidin-3-yl,1,8a-dihydroimidazo[1,2-a]pyrimidin-1-yl, 1H-pyrazolo[4,3-d]oxazol-1-yl,4H-imidazo[4,5-d]thiazol-4-yl etc.) and also include 6-memberednitrogen-containg unsaturated heterocyclic groups such as1,4-dihydropyridin-1-yl, 1,2-dihydropyridin-1-yl. These unsaturatedheterocyclic groups may have 1 to 3 substituents at any positionsthereon. These substituents are exemplified by aliphatic chainhydrocarbon groups, alicyclic hydrocarbon groups, aryl groups, aromaticheterocyclic groups, non-aromatic heterocyclic groups, halogen atoms,nitro groups, amino groups which may be substituted or unsubstituted,acyl groups which may be substituted or unsubstituted, hydroxyl groupswhich may be substituted or unsubstituted, thiol groups which may besubstituted or unsubstituted and carboxyl groups which may beesterified.

Such aliphatic chain hydrocarbon groups include linear or branchedaliphatic hydrocarbon groups such as alkyl groups, preferably thosehaving 1 to 10 carbon atoms, alkenyl groups, preferably those having 2to 10 carbon atoms, and alkynyl groups.

Preferable alkyl groups include methyl, ethyl, propyl, isopropyl, butyl,isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl,tert-pentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl,2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl, hexyl, pentyl,octyl, nonyl and decyl.

Preferable alkenyl groups include vinyl, allyl, isopropenyl, 1-propenyl,2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-ethyl-1-butenyl,3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl,4-methyl-3-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl and5-hexenyl.

Preferable alkynyl groups include ethynyl, 1-propynyl, 2-propynyl,1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl,4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl and 5-hexynyl.

Such alicyclic hydrocarbon groups include saturated or unsaturatedalicyclic hydrocarbons such as cycloalkyl groups, cycloalkenyl groupsand cycloalkadienyl groups.

Preferable cycloalkyl groups include cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[2.2.1]heptyl,bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, bicyclo[3.2.2]nonyl,bicyclo[3.3.1]nonyl, bicyclo[4.2.1]nonyl and bicyclo[4.3.1]decyl.

Preferable cycloalkenyl groups include 2-cyclopenten-1-yl,3-cyclopenten-1-yl, 2-cyclohexen-1-yl and 3-cyclohexen-1-yl.

Preferable cycloalkadienyl groups include 2,4-cyclopentadien-1-yl,2,4-cyclohexadien-1-yl and 2,5-cyclohexadien- 1-yl.

Such aryl groups are monocyclic or condensed polycyclic aromatichydrocarbon groups, preferably phenyl, naphthyl, anthryl, phenanthryl,acenaphthylenyl and others, with greater preference given to phenyl,1-naphthyl, 2-naphthyl and others.

Preferable aromatic heterocyclic groups include aromatic monocyclicheterocyclic groups such as furyl, thienyl, pyrrolyl, oxazolyl,isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl,1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, furazanyl,1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl,1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl, pyridazinyl,pyrimidinyl, pyrazinyl and triazinyl, and aromatic condensedheterocyclic groups such as benzofuranyl, isobenzofuranyl,benzo[b]thienyl, indolyl, isoindolyl, 1H-indazolyl, benzimidazolyl,benzoxazolyl, 1,2-benzisoxazolyl, benzothiazolyl, 1,2-benzisothiazolyl,1H-benzotriazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl,quinoxalinyl, phthalazinyl, naphthylizinyl, purinyl, pteridinyl,carbazolyl, α-carbolinyl, β-carbolinyl, γ-carbolinyl, acridinyl,phenoxazinyl, phenothiazinyl, phenazinyl, phenoxthinyl, thianthrenyl,phenanthridinyl, phenanthrolinyl, indolizinyl,pyrrolo[1,2-b]pyridazinyl, pyrazolo[1,5-a]pyridyl,imidazo[1,2-a]pyridyl, imidazo[1,5-a]pyridyl, imidazo[1,2-b]pyridazinyl,imidazo[1,2-a]pyrimidinyl, 1,2,4-triazolo[4,3-a]pyridyl and1,2,4-triazolo[4,3-b]pyridazinyl.

Preferable non-aromatic heterocyclic groups include oxylanyl,azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl,thiolanyl, piperidyl, tetrahydropyranyl, morpholinyl, thiomorpholinyland piperazinyl.

Such halogen atoms include atoms of fluorine, chlorine, bromine andiodine, with preference given to atoms of fluorine and chlorine.

Such amino groups include amino groups (--NH₂ groups) substituted with 1or 2 alkyl groups having 1 to 10 carbon atoms, alkenyl groups having 1to 10 carbon atoms, aromatic groups or an acyl group having one to tencarbon atoms (e.g., methylamino, dimethylamino, ethylamino,diethylamino, dibutylamino, diallylamino, cyclohexylamino, phenylamino,N-methyl-N-phenylamino, acetylamino, propionylamino, benzoylamino etc.).

Such acyl groups include formyl and groups resulting from binding of analkyl group having 1 to 10 carbon atoms, alkenyl group having 1 to 10carbon atoms or aromatic group and a carbonyl group (e.g., acetyl,propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl,heptanoyl, octanoyl, cyclobutanoyl, cyclopentanoyl, cyclohexanoyl,cycloheptanoyl, crotonyl, 2-cyclohexenecarbonyl, benzoyl, nicotinoyl).

Such hydroxyl groups include the hydroxyl group and hydroxyl groupshaving an appropriate substituent, particularly a substituent for use asa hydroxyl group protecting group, such as alkoxy, alkenyloxy,aralkyloxy and acyloxy, as well as aryloxy. Said alkoxy is preferably analkoxy having 1 to 10 carbon atoms (e.g., methoxy, ethoxy, propoxy,isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentoxy,isopentoxy, neopentoxy, hexyloxy, heptyloxy, nonyloxy, cyclobutoxy,cyclopentoxy, cyclohexyloxy). Said alkenyloxy is exemplified byalkenyloxys having 1 to 10 carbon atoms such as allyloxy, crotyloxy,2-pentenyloxy, 3-hexenyloxy, 2-cyclopentenylmethoxy and2-cyclohexenylmethoxy. Said aralkyloxy is exemplified by phenyl-C₁₋₄alkyloxys (e.g., benzyloxy, phenethyloxy). Said acyloxy is preferably analkanoyloxy having 2 to 4 carbon atoms (e.g., acetyloxy, propionyloxy,n-butyryloxy, isobutyryloxy). Said aryloxy is exemplified by phenoxy and4-chlorophenoxy.

Such thiol groups include the thiol group and thiol groups having anappropriate substituent, particularly a substituent for use as a thiolgroup protecting group, such as alkylthio, aralkylthio and acylthio.Said alkylthio is preferably an alkylthio having 1 to 10 carbon atoms(e.g., methylthio, ethylthio, propylthio, isopropylthio, butylthio,isobutylthio, sec-butylthio, tert-butylthio, pentylthio, isopentylthio,neopentylthio, hexylthio, heptylthio, nonylthio, cyclobutylthio,cyclopentylthio, cyclohexylthio). Said aralkylthio is exemplified byphenyl-C₁₋₄ alkylthios (e.g., benzylthio, phenethylthio). Said acylthiois preferably an alkanoylthio having 2 to 4 carbon atoms (e.g.,acetylthio, propionylthio, n-butyrylthio, isobutyrylthio).

Such carboxyl groups include carboxyl groups, alkyloxycarbonyl groupsand aralkyloxycarbonyl groups.

The alkyl group in said alkyloxycarbonyl groups is exemplified by alkylgroups having 1 to 6 carbon atoms, such as methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl and tert-butyl.

The aralkyl group in said aralkyloxycarbonyl groups is an alkyl grouphaving an aryl group as a substituent (arylalkyl group). Said aryl groupis exemplified by phenyl and naphthyl, each of which may have the samesubstituents as specified for the aryl group on ring R above. Said alkylgroup is preferably a lower alkyl group having 1 to 6 carbon atoms.Preferable aralkyl groups include benzyl, phenethyl, 3-phenylpropyl,(1-naphthyl)methyl and (2-naphthyl)methyl, with preference given tobenzyl, phenetyl and others.

The above-described aliphatic chain hydrocarbon groups, alicyclichydrocarbon groups, aryl groups, heterocyclic groups and others may eachhave 1 or more, preferably 1 to 3, appropriate substituents. Thesesubstituents include lower alkyl groups, lower alkenyl groups, loweralkynyl groups, cycloalkyl groups, aryl groups, aromatic heterocyclicgroups, non-aromatic heterocyclic groups, aralkyl groups, amino groups,N-mono-substituted amino groups, N,N-di-substituted amino groups,amidino groups, acyl groups, carbamoyl groups, N-mono-substitutedcarbamoyl groups, N,N-di-substituted carbamoyl groups, sulfamoyl groups,N-mono-substituted sulfamoyl groups, N,N-di-substituted sulfamoylgroups, carboxyl groups, lower alkoxycarbonyl groups, hydroxyl groups,lower alkoxy groups, lower alkenyloxy groups, cycloalkyloxy groups,aralkyloxy groups, aryloxy groups, mercapto groups, lower alkylthiogroups, aralkylthio groups, arylthio groups, sulfo groups, cyano groups,azide groups, nitro groups, nitroso groups and halogens.

With respect to general formulas (I) and (II), provided that Y is aquinoline derivative represented by C--G, the carboxyl group for G,which may be esterified, is exemplified by the carboxyl group,alkyloxycarbonyl group and aralkyloxycarbonyl group. The alkyl group insaid alkyloxycarbonyl group is exemplified by alkyl groups having 1 to 6carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl and tert-butyl.

The aralkyl group in said aralkyloxycarbonyl group is an alkyl grouphaving an aryl group as a substituent (arylalkyl group). Said aryl groupis exemplified by phenyl and naphthyl, which may have the samesubstituents as those contained in the aryl group for ring R above. Saidalkyl group is preferably a lower alkyl group having 1 to 6 carbonatoms. Such preferable aralkyl groups include benzyl, phenethyl,3-phenylpropyl, (1-naphthyl)methyl and (2-naphthyl)methyl, withpreference given to benzyl, phenetyl and others.

With respect to general formula (II), the leaving group for Q isexemplified by halogen atoms, preferably atoms of chlorine, bromine andiodine, hydroxyl groups esterificated by organic sulfonic acid residues(e.g., p-toluenesulfonyloxy group, methanesulfonyloxy group) and organicphosphoric acid residues such as the diphenylphosphoryloxy group,dibenzylphosphoryloxy group and dimethylphosphoryloxy group.

With respect to general formulas (I) and (II), rings A and B may havesubstituents. These substituents are exemplified by halogen atoms, nitrogroups, alkyl groups which may be substituted for, hydroxyl groups whichmay be substituted or unsubstituted, thiol groups which may besubstituted for, amino groups which may be substituted or unsubstituted,acyl groups which may be substituted or unsubstituted, carboxyl groupswhich may be esterified and aromatic ring groups which may besubstituted or unsubstituted. Such substituent halogen atoms includeatoms of fluorine, chlorine, bromine and iodine, with preference givento atoms of fluorine and chlorine. The alkyl group which may besubstituted for may be any one having 1 to 10 carbon atoms, whetherlinear, branched or cyclic, exemplified by methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl,neopentyl, hexyl, heptyl, octyl, nonyl, decyl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl and cycloheptyl. The hydroxyl group which may besubstituted or unsubstituted is exemplified by the hydroxyl group andhydroxyl groups having an appropriate substituent, particularly asubstituent used as a hydroxyl group protecting group, such as alkoxy,alkenyloxy, aralkyloxy and acyloxy, as well as aryloxy. Said alkoxy ispreferably an alkoxy having 1 to 10 carbon atoms (e.g., methoxy, ethoxy,propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy,pentoxy, isopentoxy, neopentoxy, hexyloxy, heptyloxy, nonyloxy,cyclobutoxy, cyclopentoxy, cyclohexyloxy). Said alkenyloxy isexemplified by alkenyloxys having 1 to 10 carbon atoms such as allyloxy,crotyloxy, 2-pentenyloxy, 3-hexenyloxy, 2-cyclopentenylmethoxy and2-cyclohexenylmethoxy. The aralkyloxy is exemplified by phenyl-C₁₋₄alkyloxys (e.g., benzyloxy, phenethyloxy). Said acyloxy is preferably analkanoyloxy having 2 to 4 carbon atoms (e.g., acetyloxy, propionyloxy,n-butyryloxy, isobutyryloxy). Said aryloxy is exemplified by phenoxy and4-chlorophenoxy. The thiol group which may be substituted orunsubstituted is exemplified by the thiol group and thiol groups havingan appropriate substituent, particularly a substituent used as a thiolgroup protecting group, such as alkylthio, aralkylthio and acylthio.Said alkylthio is preferably an alkylthio having 1 to 10 carbon atoms(e.g., methylthio, ethylthio, propylthio, isopropylthio, butylthio,isobutylthio, sec-butylthio, tert-butylthio, pentylthio, isopentylthio,neopentylthio, hexylthio, heptylthio, nonylthio, cyclobutylthio,cyclopentylthio, cyclohexylthio). Said aralkylthio is exemplified byphenyl-C₁₋₄ alkylthios (e.g., benzylthio, phenethylthio). Said acylthiois preferably an alkanoylthio having 2 to 4 carbon atoms (e.g.,acetylthio, propionylthio, n-butyrylthio, isobutyrylthio). The aminogroup which may be substituted or unsubstituted is exemplified by aminogroups (--NH₂ groups) substituted for by 1 or 2 of alkyl groups having 1to 10 carbon atoms, alkenyl groups having 1 to 10 carbon atoms, aromaticgroups and an acyl group having one to ten carbon atoms (e.g.,methylamino, dimethylamino, ethylamino, diethylamino, dibutylamino,diallylamino, cyclohexylamino, phenylamino, N-methyl-N-phenylamino,acetylamino, propionylamino, benzoylamino etc.). The acyl group whichmay be substituted or unsubstituted is exemplified by formyls and groupsresulting from binding of an alkyl group having 1 to 10 carbon atoms,alkenyl group having 1 to 10 carbon atoms or aromatic group and acarbonyl group (e.g., acetyl, propionyl, butyryl, isobutyryl, valeryl,isovaleryl, pivaloyl, hexanoyl, heptanoyl, octanoyl, cyclobutanoyl,cyclopentanoyl, cyclohexanoyl, cycloheptanoyl, crotonyl,2-cyclohexenecarbonyl, benzoyl, nicotinoyl). The carboxyl group whichmay be esterified is exemplified by carboxyl groups, alkyloxycarbonylgroups and aralkylcarbonyl groups. The alkyl group in saidalkyloxycarbonyl group is exemplified by alkyl groups having 1 to 6carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl and tert-butyl.

The aralkyl group in said aralkyloxycarbonyl group is an alkyl grouphaving an aryl group as a substituent (arylalkyl group). The aryl groupis exemplified by phenyl and naphthyl, which may have the samesubstituents as those contained in the aryl group for ring R above. Saidalkyl group is preferably a lower alkyl group having 1 to 6 carbonatoms. Preferable aralkyl groups include benzyl, phenetyl,3-phenylpropyl, (1-naphthyl)methyl and (2-naphthyl)methyl, withpreference given to benzyl, phenetyl and others. The aromatic ring groupwhich may be substituted for is exemplified by aromatic heterocyclicresidues such as pyridyl, furyl, thienyl, imidazolyl and thiazolyl, aswell as C₆₋₁₄ aromatic hydrocarbon residues such as phenyl, naphthyl andanthryl.

Such substituents for rings A and B may be present at any positions ofeach ring, and 1 to 4 substituents, whether identical or not, may bepresent on each ring. Provided that substituents on ring A or B aremutually adjacent, they may bind together to form a ring represented by--(CH₂)_(m) -- (m represents an integer from 3 to 5) or --O--(CH₂)_(l)--O--(l represents an integer from 1 to 3), ring which may be a 5- to7-membered ring formed in cooperation with carbon atoms on the benzenering.

The salt of compound (I), the desired compound of the present invention,is preferably a pharmaceutically acceptable salt, exemplified by saltswith inorganic bases, salts with organic bases, salts with inorganicacids, salts with organic acids and salts with basic or acidic aminoacids. Preferable salts with inorganic base include alkali metal saltssuch as sodium salt and potassium salt, alkaline earth metal salts suchas calcium salt and magnesium salt, aluminum salt and ammonium salt.Preferable salts with organic base include salts with trimethylamine,triethylamine, pyridine, picoline, ethanolamine, diethanolamine,triethanolamine, dicyclohexylamine and N,N'-dibenzylethylenediamine.Preferable salts with inorganic acid include salts with hydrochloricacid, hydrobromic acid, nitric acid, sulfuric acid and phosphoric acid.Preferable salts with organic acid include salts with formic acid,acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaricacid, maleic acid, citric acid, succinic acid, malic acid,methanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid.Preferable salts with basic amino acid include salts with arginine,lysine and ornithine. Preferable salts with acidic amino acid includesalts with aspartic acid and glutamic acid.

Compound (I), the desired compound of the present invention, can beadministered orally or non-orally, along with a pharmaceuticallyacceptable carrier, in the form of solid preparations such as tablets,capsules, granules and powders, or liquid preparations such as syrupsand injectable preparations.

Pharmaceutically acceptable carriers are various organic or inorganiccarrier substances in common use as pharmaceutical materials, includingexcipients, lubricants, binders and disintegrating agents for solidpreparations, and solvents, dissolution aids, suspending agents,isotonizing agents, buffers and soothing agents for liquid preparations.Other pharmaceutical additives such as preservatives, antioxidants,coloring agents and sweetening agents may be used as necessary.Preferable excipients include lactose, sucrose, D-mannitol, starch,crystalline cellulose and light silicic anhydride. Preferable lubricantsinclude magnesium stearate, calcium stearate, talc and colloidal silica.Preferable binders include crystalline cellulose, sucrose, D-mannitol,dextrin, hydroxypropyl cellulose, hydroxypropylmethyl cellulose andpolyvinylpyrrolidone. Preferable disintegrating agents include starch,carboxymethyl cellulose, carboxymethyl cellulose calcium,crosscalmellose sodium and carboxymethyl starch sodium. Preferablesolvents include water for injection, alcohol, propylene glycol,macrogol, sesame oil and corn oil. Preferable dissolution aids includepolyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate,ethanol, trisaminomethane, cholesterol, triethanolamine, sodiumcarbonate and sodium citrate. Preferable suspending agents includesurfactants such as stearyltriethanolamine, sodium lauryl sulfate,laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethoniumchloride and monostearic glycerol, and hydrophilic polymers such aspolyvinyl alcohol, polyvinylpyrrolidone, carboxymethyl cellulose sodium,methyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose andhydroxypropyl cellulose. Preferable isotonizing agents include sodiumchloride, glycerol and D-mannitol. Preferable buffers include phosphate,acetate, carbonate or citrate buffer solutions. Preferable soothingagents include benzyl alcohol. Preferable preservatives includep-oxybenzoates, chlorobutanol, benzyl alcohol, phenethyl alcohol,dehydroacetic acid and sorbic acid. Preferable antioxidants includesulfites and ascorbic acid.

Compound (I) can, for example, be produced as follows: ##STR7## whereinthe symbols have the same definitions as above.

In this method, compound (II) is reacted with compound (III) in thepresence of a base to yield compound (I). The reaction of compounds (II)and (III) is carried out in an appropriate solvent. Said solvent isexemplified by aromatic hydrocarbons such as benzene, toluene andxylene, ethers such as dioxane, tetrahydrofuran and dimethoxyethane,alcohols such as methanol, ethanol and propanol, ethyl acetate,acetonitrile, pyridine, N,N-dimethylformamide, dimethylsulfoxide,chloroform, dichloromethane, 1,2-dichloroethane,1,1,2,2-tetrachloroethane, acetone, 2-butanone and mixtures thereof. Thereaction of compounds (II) and (III) is carried out in the presence ofan appropriate base exemplified by alkali metal salts such as sodiumhydroxide, potassium carbonate, sodium carbonate and sodium hydrogencarbonate, mines such as pyridine, triethylamine andN,N-dimethylaniline, sodium hydride and potassium hydride. The amount ofthese bases used is preferably about 1 to 5 mol per mol of compound(II). This reaction is carried out at temperatures normally between -20°and 150° C., preferably between about -10° and 100° C.

Quinoline or quinazoline derivative (I) thus obtained can be isolatedand purified by known means of separation and purification such asordinary concentration, concentration under reduced pressure, solventextraction, crystallization, recrystallization, redissolution andchromatography.

Starting material compound (II) for the present invention can, forexample, be produced as follows: ##STR8## wherein G' represents anesterified carboxyl group; the symbols have the same definitions asabove. The esterified carboxyl group for G' is exemplified by the sameesterified carboxyl groups specified for G above.

In this method, 2-aminobenzophenone derivative (IV) is reacted withcompound (V) in the presence of an acid to yield compound (II-1). Thereaction of compounds (IV) and (V) is carried out in an appropriatesolvent. This solvent is exemplified by aromatic hydrocarbons such asbenzene, toluene and xylene, ethers such as dioxane, tetrahydrofuran anddimethoxyethane, N,N-dimethylformamide, dimethylsulfoxide, chloroform,dichloromethane, 1,2-dichloroethane, 1,1,2,2-tetrachloroethane andacetic acid. The reaction of compounds (IV) and (V) is carried out inthe presence of an appropriate acid such as a Lewis acid such asaluminum chloride or zinc chloride, or sulfuric acid or trifluoroaceticacid. The amount of these acids used about 0.01-2.0 mol, preferablyabout 0.05 to 0.5 tool per mol of compound (IV). This reaction iscarried out at temperatures normally between 20° and 200° C., preferablybetween about 30° and 150° C. Reaction time is 0.5 to 20 hours,preferably 1 to 10 hours.

Compound (II-1) thus obtained can be isolated and purified by knownmeans of separation and purification such as ordinary concentration,concentration under reduced pressure, solvent extraction,crystallization, recrystallization, redissolution and chromatography.##STR9## wherein the symbols have the same definitions as above.

In this method, 2-aminobenzophenone derivative (IV) is reacted withacetoacetic acid ester derivative (VI) in the presence of an acid toyield compound (VII), which is then brominated to 2-bromomethylquinolinederivative (II-2). The reaction of compounds (IV) and (VI) is carriedout in the same manner as method B. Bromination of compound (VII) iscarried out in an appropriate solvent by a conventional method. Thissolvent is exemplified by halogenated hydrocarbons such as carbontetrachloride, chloroform, dichloromethane, 1,2-dichloroethane and1,1,2,2-tetrachloroethane. Bromination of compound (VII) is carried outin the presence of a radical reaction initiator such as benzoyl peroxideor 2,2'-azobis(isobutyronitrile). The amount of these radical reactioninitiators used is preferably about 0.001 to 0.01 equivalent mol per molof compound (VII). This reaction is carried out at temperatures normallybetween 20° and 150° C., preferably between about 30° and 100° C.Reaction time is 0.5 to 20 hours, preferably 1 to 10 hours.

Compound (II-2) thus obtained can be isolated and purified by knownmeans of separation and purification such as ordinary concentration,concentration under reduced pressure, solvent extraction,crystallization, recrystallization, redissolution and chromatography.##STR10## wherein Q' represents a halogen atom; the symbols have thesame definitions as above. With respect to formulas (VIII) and (II-3),the halogen atom for Q' is exemplified by atoms of chlorine, bromine andiodine.

In this method, 2-aminobenzophenone derivative (IV) is reacted withhalogenoacetonitrile derivative (VIII) to yield2-halogenomethylquinazoline derivative (II-3). The reaction of compounds(IV) and (VIII) is carried out in an excess amount of compound (VIII) asa solvent in the presence of an acid. This acid is exemplified by thesame acids as specified for method B above. The amount of these acidsused is about 1 to 5 equivalent mol, preferably 1 to 2 mol per mol ofcompound (IV). Reaction time is 0.5 to 30 hours, preferably 1 to 10hours. Reaction temperature is normally between 20° and 200° C.,preferably between about 30° and 150° C.

Quinazoline derivative (II-3) thus obtained can be isolated and purifiedby known means of separation and purification such as ordinaryconcentration, concentration under reduced pressure, solvent extraction,crystallization, recrystallization, redissolution and chromatography.##STR11## wherein the symbols have the same definitions as above.

In this method, 2-aminobenzophenone derivative (IV) is reacted withacetonitrile to yield 2-methylquinazoline derivative (IX), which is thenbrominated to 2-bromomethylquinazoline derivative (II-4). The reactionof compound (IV) and acetonitrile is carried out in the same manner asmethod D. Bromination of compound (IX) is carried out in the same manneras the bromination of compound (VII) by method C.

Quinazoline derivative (II-4) thus obtained can be isolated and purifiedby known means of separation and purification such as ordinaryconcentration, concentration under reduced pressure, solvent extraction,crystallization, recrystallization, redissolution and chromatography.##STR12## wherein the symbols have the same definitions as above.

In this method, 2-aminobenzophenone derivative (IV) is reacted withcyanoacetic acid ester derivative (X) to yield quinazoline derivative(XI). The reaction of compounds (IV) and (X) is carried out in the samemanner as method D.

Quinazoline derivative (XI) thus obtained can be isolated and purifiedby known means of separation and purification such as ordinaryconcentration, concentration under reduced pressure, solvent extraction,crystallization, recrystallization, redissolution and chromatography.##STR13## wherein the symbols have the same definitions as above.

In this method, 2-aminobenzophenone derivative (IV) is reacted withacetonedicarboxylic acid ester derivative (XII) to yield quinolinederivative (XIII). The reaction of compounds (IV) and (XII) is carriedout in the same manner as method B.

Quinoline derivative (XIII) thus obtained can be isolated and purifiedby known means of separation and purification such as ordinaryconcentration, concentration under reduced pressure, solvent extraction,crystallization, recrystallization, redissolution and chromatography.##STR14## wherein Y' represents a nitrogen atom or C--G'; the symbolshave the same definitions as above.

In this method, compounds (XI) and (XIII) as obtained by methods F andG, respectively, are subjected to a reducing reaction to yield alcohol(XIV). This reduction can be carried out by known methods such asreduction with metal hydride, reduction with metal-hydrogen complexcompound, reduction with diborane or substituted diborane and catalytichydrogenation. In other words, this reaction is carried out by treatingcompounds (XI) and (XIII) with a reducing agent. Reducing agents includemetal-hydrogen complex compounds such as alkali metal borohydrides(e.g., sodium borohydride, lithium borohydride) and lithium aluminumhydride, metal-hydrogen compounds such as sodium hydride, organic tincompounds (e.g., triphenyltin hydride), nickel compounds, zinc compoundsand other metal or metal salt compounds, catalytic reducing agentsconsisting of a combination of hydrogen and a transition metal catalystsuch as palladium, platinum or rhodium, and diborane. This reaction iscarried out in an organic solvent which does not interfere with thereaction. This solvent is exemplified by aromatic hydrocarbons such asbenzene, toluene and xylene, halogenated hydrocarbons such aschloroform, carbon tetrachloride, dichloromethane, 1,2-dichloroethaneand 1,1,2,2-tetrachloroethane, ethers such as diethyl ether,tetrahydrofuran and dioxane, alcohols such as methanol, ethanol,propanol, isopropanol and 2 -methoxyethanol, amides such asN,N-dimethylformamide and mixtures thereof chosen as appropriateaccording to the kind of reducing agent. This reaction is carried out attemperatures normally between -20° and 150° C., preferably between 0°and 100° C., reaction time being about 1 to 24 hours. ##STR15## whereinthe symbols have the same definitions as above.

In this method, compound (XIV) is reacted with a halogenating agent or asulfonylating agent to yield compound (II-5). Preferable halogenatingagents for this purpose include thionyl chloride and phosphorustribromide. When such halogenating agents are used, compound (II-5)wherein Q is chlorine or bromine is produced. This reaction is carriedout in an appropriate inert solvent (e.g., benzene, toluene, xylene,chloroform, dichloromethane) or in an excess amount of halogenatingagent as a solvent at -10° to 80° C. The amount of halogenating agentused is 1 to 20 mol per tool of compound (XIV). Preferable sulfonylatingagents for this purpose include mesyl chloride, tosyl chloride andbenzenesulfonyl chloride. When such sulfonylating agents are used,compound (II-5) wherein Q is mesyloxy, tosyloxy or benzenesulfonyloxy,respectively, is produced. This reaction is carried out in anappropriate inert solvent (e.g., benzene, toluene, xylene, ethyl ether,ethyl acetate, tetrahydrofuran, chloroform, dichloromethane) in thepresence of a base (e.g., triethylamine, N-methylmorpholine, sodiumhydrogen carbonate, potassium hydrogen carbonate, sodium carbonate,potassium carbonate) at -10° to 30° C. The amount of sulfonylating agentor base used is 1 to 1.2 tool per tool of compound (XIV). It is possibleto produce compound (II-5) wherein Q is iodine by reacting 1 mol ofthus-obtained compound (II-5) wherein Q is chlorine, bromine orsulfonyloxy with 1 to 1.5 tool of sodium iodide or potassium iodide. Inthis case, the reaction can be carried out in a solvent such as acetone,methyl ethyl ketone, methanol or ethanol at 20° to 80° C. ##STR16##wherein the symbols have the same definitions as above.

In this method, compounds (II-1), (II-2), (II-3), (II-4) and (II-5) asproduced by methods B, C, D, E and I, respectively, are oxidized toyield compound (lI-6). This oxidation is carried out in the presence ofan oxidizing agent such as m-chloroperbenzoic acid, hydrogen peroxide,perester or sodium metaperiodate in accordance with a conventionalmethod. This oxidation is advantageously carried out in an organicsolvent inert under the reaction conditions, such as a halogenatedhydrocarbon (e.g., methylene chloride, chloroform, dichloroethane), ahydrocarbon (e.g., benzene, toluene) or an alcohol (e.g., methanol,ethanol, propanol). The amount of oxidizing agent used is 1 to 5equivalent mol, preferably 1 to 3 equivalent tool per tool of compound(II-1), (II-2), (II-3), (II-4) or (II-5). Reaction temperature isbetween -10° and 150° C., preferably between about 0° and 100° C.,reaction time being normally 0.5 to 10 hours.

Quinoline 1-oxide or quinazoline 1-oxide derivative (II-6) thus obtainedcan be isolated and purified by known means of separation andpurification such as ordinary concentration, concentration under reducedpressure, solvent extraction, crystallization, recrystallization,redissolution and chromatography.

Compound (I) can also be produced by the following methods K, L and M.##STR17## wherein the symbols have the same definitions as above.

In this method, compound (IV) is first reacted with compound (XV) toyield compound (I-1). The reaction of compounds (IV) and (XV) is carriedout in the same manner as method B.

Compound (I-2) is then oxidized to compound (I-2). This oxidizingreaction is carried out in the same manner as method J. ##STR18##wherein the symbols have the same definitions as above.

In this method, compounds (I-1) and (I-2) are hydrolyzed to carboxylicacid derivative (I-3). This hydrolysis is carried out in water or ahydrated solvent by a conventional method. Said hydrated solvent is amixture of water and an alcohol (e.g., methanol, ethanol), ether (e.g.,tetrahydrofuran, dioxane), N,N-dimethylformamide, dimethylsulfoxide,acetonitrile or acetone.

This reaction is carried out in the presence of a base such as potassiumcarbonate, sodium carbonate, potassium hydroxide, sodium hydroxide orlithium or an acid such as hydrochloric acid, sulfuric acid, acetic acidor hydrobromic acid. Preferably, the acid or base is used in excess (1.2to 6 equivalents for base, 2 to 50 equivalents for acid) per mol ofcompound (I-1) or (I-2). This reaction is carried out at temperaturesbetween -20° and 150° C., preferably between -10° and 100° C.

Method M

In this method, compound (I) wherein rings A and B have an isopropoxysubstituent is treated with titanium tetrachloride, titaniumtrichloride, boron trichloride, silicon tetrachloride or the like toconvert the isopropoxy group to a hydroxyl group to yield compound (I-4)wherein rings A and B have a phenolic hydroxyl group as a substituent.

This reaction is carried out in an appropriate solvent. This solvent isexemplified by carbon tetrachloride, dichloromethane, chloroform,1,2-dichloroethane, 1,1,2,2-tetrachloroethane and acetonitrile andmixtures thereof. The mount of titanium tetrachloride, borontrichloride, silicon tetrachloride etc. used is 1 to 10 equivalent mol,preferably 1 to 6 equivalent mol per isopropoxy group. This reaction iscarried out at temperatures between -50° and 100° C., preferably between-20° and 80° C.

Compound (I) or a salt thereof as provided by the present invention,exhibiting anti-inflammatory action and antipyretic analgesic action,was shown to have excellent anti-arthritic action in an experimentalmodel of adjuvant arthritis showing arthritic symptoms similar to thosein human rheumatoid arthritis. The compound of the present invention isof low toxicity; for example, no deaths occurred in mice orally dosedwith the compound synthesized in Example 2 or 16 at 100 mg/kg or in ratsorally dosed with the compound synthesized in Example 16 at 200 mg/kg.With these features, the desired compounds of the present invention areapplicable to all forms of arthritis showing inflammatory symptoms inthe joint.

Although the dose of compound (I) of the present invention is variableaccording to the route of administration and symptoms of the subjectpatient, it can range from 5 to 1,000 mg for oral administration or from1 to 100 mg for non-oral administration, both for adults, and this dailydose may be administered in 1 to 3 portions.

A method of testing the pharmacologic action of compound (I) of thepresent invention is described below. The results of such a test arealso given below.

TEST EXAMPLE 1 Action Against Rat Adjuvant Arthritis

Male Lewis rats (7 weeks of age, Clea Japan) were sensitized byintracutaneous injection of 0.05 ml of Freund's complete adjuvant (0.5%dead tubercle bacillus cell suspension in liquid paraffin) at the righthind paw. The test drug (12.5 mg/kg), in suspension in 5% gum arabic,was once daily administered orally for 14 days starting just beforesensitization (day 0). At days 0 and 14, the animal's left hind pawvolume and body weight were measured, and percent paw swellingsuppression and percent body weight gain, relative to sensitized controlrats, were determined.

The results, expressed in mean ±S.E. for 6 animals in each group, werecompared and statistically analyzed by Dunnett's test. Level ofsignificance was set below 5%. As seen in Table 1, the compound of thepresent invention effectively suppressed paw edema and improved systemiccondition as demonstrated by body weight gain.

                  TABLE 1                                                         ______________________________________                                        Compound    Percent Swelling                                                                           Body Weight Gain.sup.1)                              (Example No.)                                                                             Suppression (%)                                                                            Rate (%)                                             ______________________________________                                        1           65**         5                                                    2           70**         21                                                   3           55**         16*                                                  16          66**         20*                                                  ______________________________________                                         ##STR19##                                                                     **;p < 0.01, p < 0.05                                                    

REFERENCE EXAMPLE 1

To a mixture of 2-amino-3',4'-dimethoxy-4,5-ethylenedioxybenzophenone(6.5 g), ethyl 4-chloroacetoacetate (3.7 g) and acetic acid (60 ml),concentrated sulfuric acid (0.3 ml) was added, followed by stirring at100° C. for 3 hours. After the reaction mixture was concentrated underreduced pressure, the residue was poured over water and alkalinized with2N NaOH and then extracted with chloroform. The chloroform layer waswashed with water and dried (MgSO₄), after which the solvent wasdistilled off under reduced pressure. The residue was subjected tosilica gel column chromatography and eluted with chloroform-ethylacetate (7:3, v/v) to yield2-chloromethyl-4-(3,4-dimethoxyphenyl)-6,7-ethylenedioxyquinoline-3-carboxylicacid ethyl ester (5.5 g, 60%), which was then recrystallized fromacetone to yield a colorless prismatic crystal having a melting point of197° to 198° C.

Elemental analysis (for C₂₃ H₂₂ NO₆ Cl): Calculated: C, 62.24; H, 5.00;N, 3.16, Found: C, 61.95; H, 5.15; N, 3.01.

REFERENCE EXAMPLES 2 THROUGH 12

The same procedure as in Reference Example 1 was followed to yield thecompounds listed in Tables 2 through 3.

REFERENCE EXAMPLE 13

To a mixture of 2-amino-4,5,3',4'-tetramethoxybenzophenone, ethylacetoacetate and acetic acid, concentrated sulfuric acid was added,followed by the same treatment as in Reference Example 1, to yield6,7-dimethoxy-4-(3,4-dimethoxyphenyl)-2-methylquinoline-3-carboxylicacid ethyl ester (83%), which was then recrystallized from ethanol toyield a colorless prismatic crystal having a melting point of 147° to148° C.

REFERENCE EXAMPLE 14

To a mixture of 2-amino-4,5,3',4'-tetramethoxybenzophenone, propylacetoacetate and acetic acid, concentratd sulfuric acid was added,followed by the same treatment as in Reference Example 1, to yield6,7-dimethoxy-4-(3,4-dimethoxyphenyl)-2-methylquinoline-3-carboxylicacid propyl ester (79%), which was then recrystallized from ethylacetate-isopropyl ether to yield a colorless prismatic crystal having amelting point of 153° to 155° C.

REFERENCE EXAMPLE 15

To a mixture of 2-amino-4,5,3',4'-tetramethoxybenzophenone, butylacetoacetate and acetic acid, concentrated sulfuric acid was added,followed by the same treatment as in Reference Example 1, to yield6,7-dimethoxy-4-(3,4-dimethoxyphenyl)-2-methylquinoline-3-carboxylicacid butyl ester (53%), which was then recrystallized from ethylacetate-hexane to yield a colorless prismatic crystal having a meltingpoint of 119° to 120° C.

REFERENCE EXAMPLE 16

A mixture of6,7-dimethoxy-4-(3,4-dimethoxyphenyl)-2-methylquinoline-3-carboxylicacid ethyl ester (411 rag), N-bromosuccinimide (214 mg),2,2'-azobis(isobutyronitrile) (10 mg) and carbon tetrachloride (10 ml)was stirred under refluxing conditions for 5 hours. The reaction mixturewas washed with water and dried (MgSO₄), after which the solvent wasdistilled off under reduced pressure. The residue was subjected tosilica gel column chromatography and eluted with chloroform-ethylacetate (10:1, v/v) to yield2-bromomethyl-6,7-dimethoxy-4-(3,4-dimethoxyphenyl)quinoline-3-carboxylicacid ethyl ester (285 mg, 58%), which was then recrystallized from ethylacetate-hexane to yield a colorless prismatic crystal having a meltingpoint of 135° to 136° C.

Elemental analysis (for C₂₃ H₂₄ NO₆ Br): Calculated: C, 56.34; H, 4.93;N, 2.86,Found: C, 55.98; H, 5.23; N, 2.62.

REFERENCE EXAMPLE 17

The same procedure as in Reference Example 16 was followed to yield2-bromomethyl-6,7-dimethoxy-4-(3,4-dimethoxyphenyl)quinoline-3-carboxylicacid propyl ester (48%), which was then recrystallized from ethylacetate-isopropyl ether to yield a colorless prismatic crystal having amelting point of 144° to 145° C.

Elemental analysis (for C₂₄ H₂₆ NO₆ Br): Calculated: C, 57.15; H, 5.20;N, 2.78, Found: C, 56.75; H, 5.30; N, 2.68.

REFERENCE EXAMPLE 18

The same procedure as in Reference Example 16 was followed to yield2-bromomethyl-6,7-dimethoxy-4-(3,4-dimethoxyphenyl)quinoline-3-carboxylicacid butyl ester (56%), which was then recrystallized from ethylacetate-ether to yield a colorless prismatic crystal having a meltingpoint of 160° to 161° C.

Elemental analysis (for C₂₅ H₂₈ NO₆ Br): Calculated: C, 57.92; H, 5.44;N, 2.70, Found: C, 57.96; H, 5.53; N, 2.50.

REFERENCE EXAMPLE 19

A mixture of2-chloromethyl-6,7-dimethoxy-4-(3,4-dimethoxyphenyl)quinoline-3-carboxylicacid ethyl ester (3.0 g), m-chloroperbenzoic acid (85%, 2.3 g) andmethanol (40 ml) was stirred under refluxing conditions for 2 hours. Thereaction mixture was distilled under reduced pressure to remove thesolvent. The residue was poured over chloroform. The chloroform layerwas washed with water and dried (MgSO₄), after which the solvent wasdistilled off under reduced pressure. The residue was subjected tosilica gel column chromatography and eluted with chloroform-ethylacetate (6:4, v/v) to yield2-chloromethyl-6,7-dimethoxy-4-(3,4-dimethoxyphenyl)quinoline-3-carboxylicacid ethyl ester 1-oxide (2.0 g, 65%), which was then recrystallizedfrom acetone-isopropyl ether to yield a colorless prismatic crystalhaving a melting point of 193° to 194° C.

Elemental analysis (for C₂₃ H₂₄ NO₇ Cl): Calculated: C, 59.81; H, 5.24;N, 3.03, Found: C, 59.69; H, 5.32; N, 3.05.

REFERENCE EXAMPLE 20

To a mixture of 2-amino-4,5,3',4'-tetramethoxybenzophenone (8.0 g) andchloroacetonitrile (25 ml), powdered aluminum chloride (6.7 g) wasadded, followed by stirring at 100° C. for 2 hours. The reaction mixturewas poured over water and extracted with chloroform. The chloroformlayer was washed with water and dried (MgSO₄), after which the solventwas distilled off. The residue was subjected to silica gel columnchromatography and eluted with chloroform-ethyl acetate (10:1, v/v) toyield 2-chloromethyl-6,7-dimethoxy-4-(3,4-dimethoxyphenyl)quinazoline(4.9 g, 52%), which was then recrystallized from acetone to yield acolorless prismatic crystal having a melting point of 183° to 184° C.

REFERENCE EXAMPLE 21

To a mixture of 2-amino-4,5,3',4'-tetramethoxybenzophenone (50.0 g),acetonedicarboxylic acid diethyl ester (35.0 g) and acetic acid (400ml), concentrated sulfuric acid (1.5 ml) was added, followed by stirringat 100° C. for 2.5 hours. The reaction mixture was concentrated underreduced pressure, and the residue was poured over water, neutralizedwith a saturated aqueous sodium hydrogen carbonate solution and thenextracted with chloroform. The chloroform layer was washed with waterand dried (MgSO₄), after which the solvent was distilled off underreduced pressure. The residual crystal was recrystallized from ethanolto yield 6,7-dimethoxy-4-(3,4-dimethoxyphenyl)-3-ethoxycarbonylquinoline-2-acetic acid ethyl ester (55.6 g, 73%) as acolorless prismatic crystal having a melting point of 146° to 147° C.

REFERENCE EXAMPLE 22

To a mixture of 2-amino-4,5,3',4'-tetramethoxybenzophenone (6.3 g) andcyanoacetic acid methyl ester (23 ml), powdered aluminum chloride (5.3g) was added, followed by stirring at 100° C. for 2.5 hours. Thereaction mixture was poured over water and extracted with ethyl acetate.The ethyl acetate layer was washed with water and dried (MgSO₄), afterwhich the solvent was distilled off. The residue was subjected to silicagel column chromatography and eluted with hexane-ethyl acetate (4:1,v/v) to yield 6,7-dimethoxy-4-(3,4-dimethoxyphenyl)quinazoline-2-aceticacid methyl ester (4.4 g, 55%), which was then recrystallized fromisopropyl ether to yield a colorless needle crystal having a meltingpoint of 152° to 153° C.

REFERENCE EXAMPLE 23

A mixture of sodium iodide (1.68 g) and 2-butanone (15 ml) was stirredat 80° C. for 1 hour, after which2-chloromethyl-6,7-dimethoxy-4-(3,4-dimethoxyphenyl)quinoline-3-carboxylicacid ethyl ester (2.68 g) was added, followed by stirring at 80° C. for12 hours. The reaction mixture was concentrated under reduced pressure,and the residue was poured over water and then extracted with ethylacetate. The ethyl acetate layer was washed with water and dried(MgSO₄), after which the solvent was distilled off under reducedpressure. The residue was subjected to silica gel column chromatographyand eluted with chloroform-ethyl acetate (1:1, v/v) toyield--6,7-dimethoxy-4-(3,4-dimethoxyphenyl)-2-iodomethylquinoline-3-carboxylicacid ethyl ester (1.4 g, 58%), which was then recrystallized from ethylacetate-hexane to yield a colorless prismatic crystal having a meltingpoint of 170° to 171° C.

REFERENCE EXAMPLE 24

A solution of6,7-dimethoxy-4-(3,4-dimethoxyphenyl)-3-ethoxycarbonylquinoline-2-aceticacid ethyl ester (5.8 g) in tetrahydrofuran (100 ml) was added drop bydrop at 0° C. to a suspension of lithium aluminum hydride (0.455 g) intetrahydrofuran (50 ml). After the reaction mixture was stirred at 0° C.for 1 hour, water (2.5 ml) was added drop by drop, followed by stirringfor 30 more minutes. After the insoluble solid was filtered off, thefiltrate was concentrated under reduced pressure. The residue wassubjected to silica gel column chromatography and eluted withchloroform-ethyl acetate (1:1, v/v) to yield6,7-dimethoxy-4-(3,4-dimethoxyphenyl)-2-(2-hydroxyethyl)quinoline-3-carboxylicacid ethyl ester (1.75 g, 33%), which was then recrystallized from ethylacetate-hexane to yield a colorless prismatic crystal having a meltingpoint of 150° to 151° C.

REFERENCE EXAMPLE 25

Phosphorus tribromide (PBr₃) (1.0 g) was added drop by drop to asolution of6,7-dimethoxy-4-(3,4-dimethoxyphenyl)-2-(2-hydroxyethyl)quinoline-3-carboxylicacid ethyl ester (1.7 g) in benzene (50 ml) at room temperature. Afterstirring at 80° C. for 1 hour, the reaction mixture was poured over icewater, neutralized with a saturated aqueous solution of sodium hydrogencarbonate and then extracted with chloroform. The chloroform layer waswashed with water and then dried (MgSO₄), after which the solvent wasdistilled off. The residue was subjected to silica gel columnchromatography and eluted with chloroform-ethyl acetate (1:1, v/v) toyield2-(2-bromoethyl)-6,7-dimethoxy-4-(3,4-dimethoxyphenyl)quinoline-3-carboxylicacid ethyl ester (0.49 g, 26%), which was then recrystallized from ethylacetate-hexane to yield a colorless prismatic crystal having a meltingpoint of 132° to 133° C.

REFERENCE EXAMPLES 26 THROUGH 32

The same procedure as in Reference Example 1 was followed to yield thecompounds listed in Table 4.

REFERENCE EXAMPLE 33

A mixture of 4-bromobutyric acid benzyl ester (23.7 g), imidazole (8.1g), potassium carbonate (14.0 g) and acetone (400 ml) was stirred underrefluxing conditions for 6 hours. After the reaction mixture was cooledto room temperature, the insoluble solid was filtered off, the filtratewas concentrated. The residual oily substance was subjected to silicagel column chromatography and eluted with ethyl acetate-methanol (20:1,v/v) to yield 4-(1-imidazolyl)butyric acid benzyl ester (7.3 g, 33%) asan oily substance.

NMR (δ ppm in CDCl₃): 2.11 (2H, m), 2.34 (2H, t, J=6.8 Hz), 3.99 (2H, t,J=6.8 Hz), 5.12 (2H, s), 6.87 (1H, S), 7.05 (1H, s), 7.30-7.40 (5H, m).

REFERENCE EXAMPLE 34

The same procedure as in Reference Example 33 was followed to yield4-(1,2,4-triazol-1-yl)butyric acid benzyl ester (yield 88%) as an oilysubstance.

NMR (δ ppm in CDCl₃): 2.14-2.42 (4H, m), 4.24 (2H, t, J=6.4 Hz), 5.13(2H, s), 7.30-7.43 (5H, m), 7.94 (1H, s), 7.99 (1H, s).

REFERENCE EXAMPLE 35

The same procedure as in Reference Example 33 was followed to yield5-(1-imidazolyl)valeric acid benzyl ester as an oily substance byreaction of 5-bromovaleric acid benzyl ester and imidazole.

NMR (δ ppm in CDCl₃): 1.55-1.90 (4H, m), 2.38 (2H, t, J=6.8 Hz), 3.93(2H, t, J=7.0 Hz), 5.11 (2H, s), 6.87 (1H, s), 7.05 (1H, s), 7.25-7.50(5H, m), 7.94 (1H, s), 7.99 (1H, s).

REFERENCE EXAMPLE 36

A mixture of 4-(1-imidazolyl)butyric acid benzyl ester (7.4 g), 5%palladium-carbon (1.0 g) and ethanol (400 ml) was catalytically reducedat room temperature under 1 atm. After the catalyst was filtered off,the filtrate was concentrated under reduced pressure, and the residualcrystal was recrystallized from ethanol, to yield4-(1-imidazolyl)butyric acid (3.4 g, 75%) as a colorless prismaticcrystal having a melting point of 125° to 126° C.

REFERENCE EXAMPLE 37

4-(1,2,4-Triazol-1-yl)butyric acid benzyl ester was catalyticallyreduced in the same manner as in Reference Example 36 to yield4-(1,2,4-triazol-1-yl)butyric acid, which was then recrystallized fromethanol to yield a colorless prismatic crystal having a melting point of137° to 138° C.

REFERENCE EXAMPLE 38

5-(1-Imidazolyl)valeric acid benzyl ester was catalytically reduced inthe same manner as in Reference Example 36 to yield5-(1-imidazolyl)valeric acid, which was then recrystallized from ethanolto yield a colorless prismatic crystal having a melting point of 157° to158° C.

REFERENCE EXAMPLE 39

To a suspension of 4-(1-imidazolyl)butyric acid (0.5 g) intetrahydrofuran (35 ml), 1,1'-carbonyldiimidazole (0.578 g) was added,followed by stirring at room temperature for 6 hours. After magnesiumsalt of malonic acid monoethyl ester [Mg(OCOCH₂ COOC₂ H₅)₂ ] (1.02 g)was added, the mixture was stirred at room temperature for 18 morehours. After the reaction mixture was concentrated under reducedpressure, the residue was dissolved in dichloromethane. Thedichloromethane layer was washed with water and dried (MgSO₄), afterwhich the solvent was distilled off. The residual oily substance wassubjected to silica gel column chromatography and eluted withchloroform-methanol (30:1, v/v) to yield 6-(1-imidazolyl)-3-oxohexanoicacid ethyl ester (0.32 g, 44%) as an oily substance.

NMR (δ ppm in CDCl₃): 1.28 (3H, t, J=7.4 Hz), 2.08 (2H, m), 2.53 (2H, t,J=6.6 Hz), 3.41 (2H, s), 4.00 (2H, t, J=6.6 Hz), 4.19 (2H, q, J=7.4 Hz),6.91 (1H, s), 7.07 (1H, s), 7.46 (1H, s).

REFERENCE EXAMPLE 40

The same procedure as in Reference Example 39 was followed to yield6-(1,2,4-triazol-1-yl)-3-oxohexanoic acid ethyl ester, as an oilysubstance, from 4-(1,2,4-triazol- 1-yl)butyric acid.

NMR (δ ppm in CDCl₃): 1.28 (3H, t, J=7.2 Hz), 2.19 (2H, m), 2.59 (2H, t,J=6.6 Hz), 3.43 (2H, s), 4.19 (2H, q, J=7.2 Hz), 4.23 (2H, t, J=6.6 Hz),7.94 (1H, s), 8.07 (1H, s).

REFERENCE EXAMPLE 41

The same procedure as in Reference Example 39 was followed to yield7-(1-imidazolyl)-3-oxoheptanoic acid ethyl ester, as an oily substance,from 5-(1-imidazolyl)valeric acid.

NMR (δ ppm in CDCl₃): 1.27 (3H, t, J=7.4 Hz), 1.50-1.90 (4H, m), 2.58(2H, t, J=6.6 Hz), 3.41 (2H, s), 3.95 (2H, t, J=7.0 Hz), 4.19 (2H, q,J=7.4 Hz), 6.90 (1H, s), 7.06 (1H, s), 7.47 (1H, s).

REFERENCE EXAMPLE 42

The same procedure as in Reference Example 1 was followed to yield2-chloromethyl-6,7-dimethoxy-4-(4-methoxy-3-propoxyphenyl)quinoline-3-carboxylic acid ethyl ester which was then recrystallized from ethanolto yield a colorless prismatic crystal having a melting point of 126° to128° C.

REFERENCE EXAMPLE 43

To a mixture of methyl6,7-dimethoxy-4-(3,4-dimethoxyphenyl)quinazoline-2-acetic acid methylester (4.0 g), sodium borohydride (1.9 g) and tetrahydrofuran (80 ml),methanol (15 ml) was added dropwise under continuous reflux, followed byrefluxing for 2 hours. The reaction mixture was poured into water andextracted with ethyl acetate. The ethyl acetate layer was washed withwater, dried (MgSO₄) and concentrated under reduced pressure to yield6,7-dimethoxy-4-(3,4-dimethoxyphenyl)-2-(2-hydroxyethyl) quinazoline(3.0 g, 81%). Recrystallization from ethyl acetate gave a colorlessneedle crystal having a melting point of 165° to 166° C.

REFERENCE EXAMPLE 44

The same procedure as in Reference Example 25 was followed to yield2-(2-bromoethyl)-6,7-dimethoxy-4-(3,4-dimethoxyphenyl) quinazoline,which was then recrystallized from ethyl acetate to yield a colorlessneedle crystal having a melting point of 166° to 167° C.

EXAMPLE 1

Oily sodium hydride (60%, 0.323 g) was added to a solution of2-ethylimidazole (0.776 g) in N,N-dimethylformamide (30 ml), followed bystirring at room temperature for 15 minutes. Then2-chloromethyl-6,7-dimethoxy-4-(3,4-dimethoxyphenyl)quinoline-3-carboxylicacid ethyl ester (3.0 g) was added. After stirring at 80° C. for 1 hour,the reaction mixture was poured over water, and the separating crystalwas collected by filtration, which was then recrystallized from ethanolto yield6,7-dimethoxy-4-(3,4-dimethoxyphenyl)-2-(2-ethylimidazol-1-ylmethyl)quinoline-3-carboxylicacid ethyl ester (2.5 g, 74%) as a colorless prismatic crystal having amelting point of 163° to 164° C.

EXAMPLES 2 THROUGH 11

The same procedure as in Example 1 was followed to yield the compoundslisted in Tables 5 and 6.

EXAMPLE 12

Oily sodium hydride (60%, 0.044 g) was added to a solution of imidazole(0.075 g) in N,N-dimethylformamide (5 ml), followed by stirring at roomtemperature for 15 minutes. Then2-(2-bromoethyl)-6,7-dimethoxy-4-(3,4-dimethoxyphenyl)quinoline-3-carboxylicacid ethyl ester (0.4 g) was added. After stirring at 80° C. for 1 hour,the reaction mixture was poured over water and extracted with ethylacetate. The ethyl acetate layer was washed with water and then dried(MgSO₄), after which the solvent was distilled off. The residue wassubjected to silica gel column chromatography and eluted with ethylacetate-methanol (10:1, v/v) to yield2-[2-(1-imidazolyl)ethyl]-6,7-dimethoxy-4-(3,4-dimethoxyphenyl)quinoline-3-carboxylicacid ethyl ester (0.295 g, 66%), which was then recrystallized fromethyl acetate-hexane to yield a colorless prismatic crystal having amelting point of 173° to 174° C.

EXAMPLES 13 THROUGH 15

The same procedure as in Example 12 was followed to yield the compoundslisted in Table 6.

EXAMPLE 16

Oily sodium hydride (60%, 0.323 g) was added to a solution of1H-1,2,4-triazole (0.558 g) in N,N-dimethylformamide (30 ml), followedby stirring at room temperature for 15 minutes. Then2-chloromethyl-6,7-dimethoxy-4-(3,4-dimethoxyphenyl)quinoline-3-carboxylicacid ethyl ester (3.0 g) was added. After stirring at 80° C. for 1 hour,the reaction mixture was poured over water and extracted with ethylacetate. The ethyl acetate layer was washed with water and then dried(MgSO₄), after which the solvent was distilled off. The residue wassubjected to silica gel column chromatography and eluted withchloroform-methanol (40:1, v/v) to yield6,7-dimethoxy-4-(3,4-dimethoxyphenyl)-2-(1,2,4-triazol-1-ylmethyl)quinoline-3-carboxylic acid ethyl ester (1.7 g, 53%), whichwas then recrystallized from ethyl acetate-hexane to yield a colorlessprismatic crystal having a melting point of 176 to 177° C.

EXAMPLE 17

From the second fraction in the column chromatography in Example 16 wasobtained 6,7-dimethoxy-4-(3,4-dimethoxyphenyl)-2-(1,2,4-triazol-4-ylmethyl)quinoline-3-carboxylic acid ethyl ester (0.07 g, 2%), whichwas then recrystallized from ethyl acetate-hexane to yield a colorlessprismatic crystal having a melting point of 226° to 227° C.

EXAMPLE 18

The same procedure as in Example 16 was followed to yield6,7-dimethoxy-4-(4-methoxyphenyl)-2-(1,2,4-triazol-1-ylmethyl)quinoline-3-carboxylicacid ethyl ester, which was then recrystallized from ethylacetate-hexane to yield a colorless prismatic crystal having a meltingpoint of 150° to 151° C.

EXAMPLE 19

From the second fraction in the column chromatography in Example 18 wasobtained6,7-dimethoxy-4-(4-methoxyphenyl)-2-(1,2,4-triazol-4-ylmethyl)quinoline-3-carboxylicacid ethyl ester, which was then recrystallized from ethylacetate-hexane to yield a colorless needle crystal having a meltingpoint of 218° to 219° C.

EXAMPLES 20 THROUGH 28

The same procedure as in Example 12 was followed to yield the compoundslisted in Table 7.

EXAMPLE 29

To a solution of6,7-dimethoxy-4-(4-isopropoxy-3-methoxyphenyl)-2-(1,2,4-triazol-1-ylmethyl)quinoline-3-carboxylicacid ethyl ester (55.6 mg) in dichloromethane (2 ml), titaniumtetrachloride (TIC14) (125 mg) was added at 0° C., followed by stirringat the same temperature for 6 hours. The reaction mixture was pouredover water and extracted with chloroform. The chloroform layer waswashed by sequential additions of a saturated aqueous sodium hydrogencarbonate solution and water and then dried (MgSO₄), after which thesolvent was distilled off. The residual oily substance was subjected tosilica gel column chromatography and eluted with ethylacetate-chloroform (3:2, v/v)to yield6,7-dimethoxy-4-(4-hydroxy-3-methoxyphenyl)-2-(1,2,4-triazol-1-ylmethyl)quinoline-3-carboxylicacid ethyl ester (24.5 mg, 48%) which was then recrystallized from ethylacetate-hexane having a melting point of 176° to 178° C.

NMR (δ ppm in CDCl₃): 0.88 (3H, t, J=7.2 Hz), 3.80 (3H, s), 3.88 (3H,s), 3.96 (2H, q, J=7.2 Hz), 4.05 (3H, s), 5.73 (2H, s), 5.80 (1H, broads), 6.80-7.06 (4H, m), 7.42 (1H, s), 7.94 (1H, s), 8.27 (1H, s).

EXAMPLES 30 THROUGH 32

The same procedure as in Example 29 was followed to yield the compoundslisted in Table 8.

EXAMPLE 33

To a solution of4-(3,4-diisopropoxyphenyl)-6,7-dimethoxy-2-(1,2,4-triazol-1-ylmethyl)quinoline-3-carboxylicacid ethyl ester (116.0 rag) in dichloromethane (2.5 ml), titaniumtetrachloride (TICl₄) (288 mg) was added at 0° C., followed by stirringat the same temperature for 6 hours. The reaction mixture was pouredover water and extracted with chloroform. The chloroform layer waswashed by sequential additions of a saturated aqueous sodium hydrogencarbonate solution and water and then dried (MgSO₄), after which thesolvent was distilled off. The residual oily substance was subjected tosilica gel column chromatography and eluted with chloroform-ethylacetate (7:3, v/v) to yield4-(3,4-dihydroxyphenyl)-6,7-dimethoxy-2-(1,2,4-triazol-1-ylmethyl)quinoline-3-carboxylicacid ethyl ester (20.0 mg, 21%) having a melting point of 122° to 124°C.

NMR (δ ppm in CDCl₃): 0.78 (3H, t, J=7.0 Hz), 3.78 (3H, s), 3.86 (2H, q,J=7.0 Hz), 4.00 (3H, s), 5.71 (2H, s), 6.60 (1H, broad s), 6.68-6.79(2H, m), 6.92 (1H, s), 6.97 (1H, d, J=8.0 Hz), 7.37 (1H, s), 7.95 (1H,s), 8.35 (1H, s), 8.70 (1H, broad s).

EXAMPLE 34

To a solution of4-(3,4-diisopropoxyphenyl)-6-isopropoxy-7-methoxy-2-(1,2,4-triazol-1-ylmethyl)quinoline-3-carboxylicacid ethyl ester (96.0 rag) in dichloromethane (1.0 ml), titaniumtetrachloride (TICl₄) (316 mg) was added at 0° C., followed by stirringat the same temperature for 10 hours. The reaction mixture was pouredover water and extracted with ethyl acetate. The ethyl acetate layer waswashed by sequential additions of a saturated aqueous sodium hydrogencarbonate solution and water and then dried (MgSO₄), after which thesolvent was distilled off. The residual oily substance was subjected tosilica gel column chromatography and eluted with ethyl acetate-methanol(10:1, v/v) to yield4-(3,4-dihydroxyphenyl)-6-hydroxy-7-methoxy-2-(1,2,4-triazol-1-ylmethyl)quinoline-3-carboxylicacid ethyl ester (19.0 mg, 26%) having a melting point of 264° to 266°C.

NMR (δ ppm in CDCl₃): 0.88 (3H, t, J=7.0 Hz), 3.93 (2H, q, J=7.0 Hz),3.94 (3H, s), 5.63 (2H, s), 6.52 (1H, dd, J=8.2 & 2.2 Hz), 6.67 (1H, d,J=2.2 Hz), 6.85 (1H, d, J=8.2 Hz), 6.98 (1H, s), 7.29 (1H, s), 7.94 (1H,s), 8.57 (1H, s), 9.17 (1H, s), 9.21 (1H, s), 10.00 (1H, s).

EXAMPLE 35

To a mixture of 2-amino-4,5,3',4'-tetramethoxybenzophenone (453 mg),6-(1-imidazolyl)-3-oxohexanoic acid ethyl ester (320 mg) and acetic acid(5 ml), concentrated sulfuric acid (0.03 ml) was added, followed bystirring at 100° C. for 2 hours. After the reaction mixture wasconcentrated under reduced pressure, the residue was poured over water,alkalinized with 2N sodium hydroxide and then extracted with chloroform.The chloroform layer was washed with water and dried (MgSO₄), afterwhich the solvent was distilled off. The residual oily substance wassubjected to silica gel column chromatography and eluted withchloroform-methanol (50:1, v/v) to yield6,7-dimethoxy-4-(3,4-dimethoxyphenyl)-2-[3-(1-imidazolyl)propyl]quinoline-3-carboxylicacid ethyl ester (310.0 mg, 43%), which was then recrystallized fromethyl acetate-hexane to yield a colorless prismatic crystal having amelting point of 164° to 165° C.

EXAMPLE 36

The same procedure as in Example 35 was followed to yield6,7-dimethoxy-4-(3,4-dimethoxyphenyl)-2-[3-(1,2,4-triazol-1-yl)propyl]quinoline-3-carboxylic acid ethyl ester, which was thenrecrystallized from ethanol to yield a colorless prismatic crystalhaving a melting point of 141° to 142° C.

EXAMPLE 37

The same procedure as in Example 35 was followed to yield6,7-dimethoxy-4-(3,4-dimethoxyphenyl)-2-[4-(1-imidazolyl)butyl]quinoline-3-carboxylicacid ethyl ester, which was then recrystallized from ethylacetate-hexane to yield a colorless prismatic crystal having a meltingpoint of 119° to 120° C.

EXAMPLE 38

A mixture of6,7-dimethoxy-4-(3,4-dimethoxyphenyl)-2-(1,2,4-triazol-1-ylmethyl)quinoline-3-carboxylicacid ethyl ester (3.0 g), 2N sodium hydroxide (15.6 ml) and ethanol (50ml) was stirred under refluxing conditions for 8 hours. The reactionmixture was cooled with ice and adjusted to pH 5 with 2N hydrochloricacid, after which it was concentrated under reduced pressure. Theresidue was dissolved in ethanol, and the insoluble substances werefiltered off. After the filtrate was concentrated, the residual oilysubstance was subjected to silica gel column chromatography and elutedwith chloroform-methanol (4:1, v/v) to yield6,7-dimethoxy-4-(3,4-dimethoxyphenyl)-2-(1,2,4-triazol-1-ylmethyl)quinoline-3-carboxylic acid (1.3 g, 46%), which was thenrecrystallized from dichloromethane-ethanol to yield a colorlessprismatic crystal having a melting point of 270° to 271° C.(decomposed).

EXAMPLE 39

Oily sodium hydride (60%, 0.156 g) was added to a solution of1H-1,2,4-triazole (0.27 g) in N,N-dimethylformamide (DMF) (20 ml),followed by stirring at room temperature for 15 minutes. Then2-chloromethyl-6,7-dimethoxy-4-(3,4-dimethoxyphenyl)quinoline-3-carboxylicacid ethyl ester 1-oxide (1.5 g) was added, followed by stirring at 80°C. for 45 minutes. The reaction mixture was poured over water andextracted with dichloromethane. The dichloromethane layer was washedwith water and then dried (MgSO₄), after which the solvent was distilledoff. The residual oily substance was subjected to silica gel columnchromatography and eluted with chloroform-methanol (30:1, v/v) to yield6,7-dimethoxy-4-(3,4-dimethoxyphenyl)-2-(1,2,4-triazol-1-ylmethyl)quinoline-3-carboxylicacid ethyl ester 1-oxide (0.8 g, 50%), which was then recrystallizedfrom dichloromethane-hexane to yield a colorless prismatic crystalhaving a melting point of 221° to 222° C.

EXAMPLE 40

The same procedure as in Example 16 was followed to yield6,7-dimethoxy-4-(3-propoxy-4-methoxyphenyl)-2-(1,2,4-triazol-1-ylmethyl)quinoline-3-carboxylicacid ethyl ester, which was then recrystallized from ethanol to yield acolorless prismatic crystal having a melting point of 127° to 128° C.

EXAMPLE 41

From the second fraction in the column chromatography in Example 40 wasobtained6,7-di-methoxy-4-(3-propoxy-4-methoxyphenyl)-2-(1,2,4-triazol-4-ylmethyl)quinoline-3-carboxylicacid ethyl ester which was then recrystallized from ethanol to yield acolorless needle crystal having a melting point of 154° to 155° C.

EXAMPLE 42

The same procedure as in Example 16 was followed to yield4-(3,4-dimethoxyphenyl)-6,7-ethylenedioxy-2-(1,2,4-triazol-1-ylmethyl)quinoline-3-carboxylic acid ethyl ester, which was thenrecrystallized from ethanol to yield a colorless needle crystal having amelting point of 138° to 140° C.

EXAMPLE 43

From the second fraction in the column chromatography in Example 42 wasobtained4-(3,4-dimethoxyphenyl)-6,7-ethylenedioxy-2-(1,2,4-triazol-4-ylmethyl)quinoline-3-carboxylicacid ethyl ester which was then recrystallized from ethanol to yield acolorless needle crystal having a melting point of 237° to 239° C.

EXAMPLE 44

The same procedure as in Example 16 was followed to yield6,7-dimethoxy-4-(3,4-dimethoxyphenyl)-2-(1,2,3-triazol-1-ylmethyl)quinoline-3-carboxylicacid ethyl ester, which was then recrystallized fromethanol-dichloroethane to yield a colorless prismatic crystal having amelting point of 195° to 196° C.

Elemental analysis (for C₂₅ H₂₆ N₄ O₆.1/4C₂ H₅ OH), Calculated: C,62.50; H, 5.66; N, 11.43, Found: C, 62.29; H, 5.53; N, 11.30.

EXAMPLE 45

From the second fraction in the column chromatography in Example 44 wasobtained6,7-dimethoxy-4-(3,4-dimethoxyphenyl)-2-(1,2,3-triazol-2-ylmethyl)quinoline-3-carboxylicacid ethyl ester, which was then recrystallized fromethanol-dichloroethane to yield a colorless prismatic crystal having amelting point of 163° to 164° C.

Elemental analysis (for C₂₅ H₂₆ N₄ O₆.1/2C₂ H₅ OH), Calculated: C,62.27; H, 5.83; N, 11.17, Found: C, 61.98; H, 5.69; N, 11.10.

EXAMPLE 46

From the second fraction in the column chromatography in Example 25 wasobtained6,7-dimethoxy-4-(3-isopropoxy-4-methoxyphenyl)-2-(1,2,4-triazol-4-ylmethyl)quinoline-3-carboxylicacid ethyl ester, which was then recrystallized from ethylacetate-hexane to yield a colorless prismatic crystal having a meltingpoint of 170° to 171° C.

EXAMPLE 47

From the second fraction in the column chromatography in Example 26 wasobtained6,7-dimethoxy-4-(4-isopropoxy-3-methoxyphenyl)-2-(1,2,4-triazol-4-ylmethyl)quinoline-3-carboxylicacid ethyl ester, which was then recrystallized from ethylacetate-hexane to yield a colorless prismatic crystal having a meltingpoint of 178° to 179° C.

EXAMPLE 48

Oily sodium hydride (60% 0.323 g) was added to a solution of2-hydroxypyridin (0.277 g) in N,N-dimethylformamide (10 ml), followed bystirring at room temperature for 15 minutes. Then2-iodomethyl-6,7-dimethoxy-4-(3,4-dimethoxyphenyl)quinoline-3-carboxylicethyl ester (1.2 g) was added. After stirring at room temperature for 8hours. The reaction mixture was poured over water and extracted withethyl acetate. The ethyl acetate layer was washed with water and thendried (MgSO₄), after which the solvent was distilled off.

The residue subjected to silica gel chromatography and eluted with ethylacetate-chloroform (10:1, v/v) to yield2-(1,2-dihydro-2-oxopyridin-1-ylmethyl)-6,7-dimethoxy-4-(3,4-dimethoxyphenyl)quinoline-3-carboxylicacid ethyl ester (0.64 g, 57%), which was then recrystallized fromethanol to a yield a colorless prismatic crystal having a melting pointof 154° to 156° C.

EXAMPLE 49

The same procedure as in Example 12 was followed to yield2-[2-(1-imidazolyl)ethyl]-6,7-dimethoxy-4-(3,4-dimethoxyphenyl)quinazoline,which was then recrystallized from ethyl acetate to yield a colorlessprismatic crystal having a melting point of 147° to 148° C.

EXAMPLE 50

The same procedure as in Example 1 was followed to yield2-(benzimidazol-1-ylmethyl)-6,7-dimethoxy-4-(3,4-dimethoxyphenyl)quinoline-3-carboxylicacid ethyl ester by reaction of2-bromomethyl-6,7-dimethoxy-4-(3,4-dimethoxyphenyl)quinoline-3-carboxylicacid ethyl ester with benzimidazole, which was then recrystallized fromethanol to yield a colorless prismatic crystal having a melting point of99° to 100° C.

EXAMPLE 51

The same procedure as in Example 16 was followed to yield6,7-dimethoxy-4-(3,4-dimethoxyphenyl)-2-(1,2,4-triazol-1-ylmethyl)quinoline-3-carboxylic acid methyl ester by reaction of2-chloromethyl-6,7-dimethoxy-4-(3,4-dimethoxyphenyl)quinoline-3-carboxylicacid methyl ester with 1H-1,2,4-triazole, which was then recrystallizedfrom ethanol to yield a colorless prismatic crystal having a meltingpoint of 218° to 220° C.

EXAMPLE 52

The same procedure as in Example 1 was followed to yield6,7-dimethoxy-4-(3,4-dimethoxyphenyl)-2-(imidazol-1-ylmethyl)quinoline-3-carboxylicacid propyl ester by reaction of2-bromomethyl-6,7-dimethoxy-4-(3,4-dimethoxyphenyl)quinoline-3-carboxylicacid propyl ester with imidazole, which was then recrystallized fromethanol to yield a colorless prismatic crystal having a melting point of166° to 168° C.

EXAMPLE 53

The same procedure as in Example 1 was followed to yield6,7-dimethoxy-4-(3,4-dimethoxyphenyl)-2-(imidazol-1-ylmethyl)quinoline-3-carboxylic acid butyl ester by reaction of2-bromomethyl-6,7-dimethoxy-4-(3,4-dimethoxyphenyl)quinoline-3-carboxylicacid butyl ester with imidazole, which was then recrystallized fromethanol to yield a colorless prismatic crystal having a melting point of140° to 141° C.

EXAMPLE 54

The same procedure as in Example 16 was followed to yield6-chloro-4-phenyl-2-(1,2,4-triazol-1-ylmethyl)quinoline-3-carboxylicacid ethyl ester by reaction of6-chloro-2-chloromethyl-4-phenylquinoline-3-carboxylic acid ethyl esterby reaction of 6-chloro-2-chloromethyl-4-phenylquinoline-3-carboxylicacid ethyl ester with 1H-1,2,4-triazole, which was then recrystallizedfrom ethanol to yield a colorless prismatic crystal having a meltingpoint of 114° to 116° C.

EXAMPLE 55 THROUGH 62

The same procedure as in Example 1 was followed to yield the compoundslisted in Table 9.

EXAMPLE 63

A solution of HCl in ethanol (23%, 0.172g) was added dropwise to asuspension of6,7-dimethoxy-4-(3-isopropoxy-4-methoxyphenyl)-2-(1,2,4-triazol-1-ylmethyl)quinoline-3-carboxylic acid ethyl ester (0.5 g) in ethanol(10ml)-dichloromethane (2 ml) at room temperature. The mixture wasstirred at the same temperature for 15 minutes and concentrated underreduced pressure. The residue was treated with isopropyl ether to yieldsolid, which was recrystallized from ethanol to yield6,7-dimethoxy-4-(3-isopropoxy-4-methoxyphenyl)-2-(1,2,4-triazol-1-ylmethyl)quinoline-3-carboxylic acid ethyl ester hydrochloride (0.211g, 39%) asyellow crystals having melting point of 93 to 95° C.

                                      TABLE 2                                     __________________________________________________________________________     ##STR20##                                                                     No.ExampleReference                                                                 R.sup.1, R.sup.2                                                                    ##STR21##                                                                              G      (%)Yield                                                                         Point (°C.)Melting                                                           SolventRecrystallization                __________________________________________________________________________    2     6-Cl, H                                                                              ##STR22##                                                                             COOC.sub.2 H.sub.5                                                                   61 105-106                                                                             Ethanol-water                            3     6-Cl, H                                                                              ##STR23##                                                                             COOC.sub.2 H.sub.5                                                                   42 140-141                                                                             Ethyl acetate-hexane                     4     6-CH.sub.3, H                                                                        ##STR24##                                                                             COOC.sub.2 H.sub.5                                                                   42  78- 79                                                                             Ethyl acetate-hexane                     5     6,7-(CH.sub.3).sub.2                                                                 ##STR25##                                                                             COOC.sub.2 H.sub.5                                                                   70 170-171                                                                             Ethyl acetate                            __________________________________________________________________________     Note 1)                                                                       NMR (δ ppm in CDCl.sub.3): 0.92(3H, t, J=7.2Hz), 4.06(2H, q,            J=7.2Hz), 5.03(2H, s), 7.33-7.37(2H, m), 7.50-7.55(3H, m), 7.90-7.98(2H,      m), 8.26(1H, d, J=9.4Hz)                                                 

                                      TABLE 3                                     __________________________________________________________________________     ##STR26##                                                                     No.ExampleReference                                                                 R.sup.1, R.sup.2                                                                       ##STR27##  G     (%)Yield                                                                          Point (°C.)Melting                                                           SolventRecrystallization           __________________________________________________________________________     6    6,7-(OCH.sub.2 CH.sub.2 O)                                                              ##STR28## COOC.sub.2 H.sub.5                                                                  44  155-156                                                                             Acetone-ether                        7    6,7-(CH.sub.3 O).sub.2                                                                  ##STR29## COOC.sub.2 H.sub.5                                                                  23  153-155                                                                             Acetone-ether                        8    6,7-(CH.sub.3 O).sub.2                                                                  ##STR30## COOC.sub.2 H.sub.5                                                                  48  108-109                                                                             Ether                                9    6,7-(CH.sub.3 O).sub.2                                                                  ##STR31## COOC.sub.2 H.sub.5                                                                  53  160-161                                                                             Ethyl acetate-hexane                10    6,7-(CH.sub.3 O).sub.2                                                                  ##STR32## COOC.sub.2 H.sub.5                                                                  35  126-127                                                                             Acetone-ether                       11    6,7-(CH.sub.3 O).sub.2                                                                  ##STR33## COOCH.sub.3                                                                         44  181-182                                                                             Acetone-ether                       12    6,7-(CH.sub.3 O).sub.2                                                                  ##STR34## COOC.sub.2 H.sub.5                                                                  53  147-148                                                                             Acetone-ether                       __________________________________________________________________________

                                      TABLE 4                                     __________________________________________________________________________     ##STR35##                                                                    Reference                                                                     Example                           Yield                                                                             Melting                                                                             Recrystallization                 No.   A.sup.1                                                                              A.sup.2                                                                              B.sup.1                                                                              B.sup.2                                                                              (%) Point (°C.)                                                                  Solvent                           __________________________________________________________________________    26    CH.sub.3 O                                                                           CH.sub.3 O                                                                           Cl     Cl     57  159-160                                                                             Ethyl acetate-hexane              27    (CH.sub.3).sub.2 CHO                                                                 CH.sub.3 O                                                                           CH.sub.3 O                                                                           CH.sub.3 O                                                                           66  138-140                                                                             Ethyl acetate-hexane              28    CH.sub.3 O                                                                           (CH.sub.3).sub.2 CHO                                                                 CH.sub.3 O                                                                           CH.sub.3 O                                                                           48  125-126                                                                             Ethyl acetate-hexane              29    CH.sub.3 O                                                                           CH.sub.3 O                                                                           (CH.sub.3).sub.2 CHO                                                                 CH.sub.3 O                                                                           50  126-127                                                                             Ethanol                           30    CH.sub.3 O                                                                           CH.sub.3 O                                                                           CH.sub.3 O                                                                           (CH.sub.3).sub.2 CHO                                                                 48  149-150                                                                             Ethanol                           31    CH.sub.3 O                                                                           CH.sub.3 O                                                                           (CH.sub.3).sub.2 CHO                                                                 (CH.sub.3).sub.2 CHO                                                                 48  118-119                                                                             Ethyl acetate-hexane              32    CH.sub.3 O                                                                           (CH.sub.3).sub.2 CHO                                                                 (CH.sub.3).sub.2 CHO                                                                 (CH.sub.3).sub.2 CHO                                                                 60   99-100                                                                             Ethyl acetate-hexane              __________________________________________________________________________

                                      TABLE 5                                     __________________________________________________________________________     ##STR36##                                                                     No.Example                                                                         ##STR37##  Y                                                                                     ##STR38##                                                                             Point (°C.)Melting                                                           SolventRecrystallization               __________________________________________________________________________          ##STR39## CCOOC.sub.2 H.sub.5                                                                    ##STR40##                                                                            208-209                                                                             Dichloro methane-hexane                 3                                                                                   ##STR41## CCOOC.sub. 2 H.sub.5                                                                   ##STR42##                                                                            177-178                                                                             Ethyl acetate-hexane                    4                                                                                   ##STR43## CCOOC.sub.2 H.sub.5                                                                    ##STR44##                                                                            134-135                                                                             Ethanol                                 5                                                                                   ##STR45## CCOOC.sub.2 H.sub.5                                                                    ##STR46##                                                                            200-201                                                                             Ethyl acetate-hexane                    6                                                                                   ##STR47## CCOOC.sub.2 H.sub.5                                                                    ##STR48##                                                                            148-149                                                                             Ethyl acetate-hexane                    7                                                                                   ##STR49## CCOOC.sub.2 H.sub.5                                                                    ##STR50##                                                                            157-158                                                                             Ethanol                                 8                                                                                   ##STR51## N                                                                                      ##STR52##                                                                            184-185                                                                             Dichloromethane-ethyl ether             9                                                                                   ##STR53## N                                                                                      ##STR54##                                                                            223-224                                                                             Dichloromethane-ethyl                   __________________________________________________________________________                                          ether                               

                                      TABLE 6                                     __________________________________________________________________________     ##STR55##                                                                     No.Example                                                                         ##STR56##  Y                                                                                     ##STR57##                                                                               Point (°C.)Melting                                                           SolventRecrystallization             __________________________________________________________________________    10                                                                                  ##STR58## N                                                                                      ##STR59##                                                                              188-189                                                                             Ethyl acetate-hexane                  11                                                                                  ##STR60## N                                                                                      ##STR61##                                                                              198-199                                                                             Dichloromethane-ethyl ether           13                                                                                  ##STR62## CCOOC.sub.2 H.sub.5                                                                    ##STR63##                                                                              209-210                                                                             Dichloromethane-hexane                14                                                                                  ##STR64## CCOOC.sub.2 H.sub.5                                                                    ##STR65##                                                                              198-199                                                                             Ethanol                               15                                                                                  ##STR66## CCOOC.sub.2 H.sub.5                                                                    ##STR67##                                                                              124-125                                                                             Ethyl acetate-hexane                  __________________________________________________________________________

                                      TABLE 7                                     __________________________________________________________________________     ##STR68##                                                                    Example                             Yield                                                                             Melting                                                                             Recrystallization               No.  A.sup.1                                                                              A.sup.2                                                                              B.sup.1                                                                              B.sup.2                                                                              W  (%) Point (°C.)                                                                  Solvent                         __________________________________________________________________________    20   CH.sub.3 O                                                                           CH.sub.3 O                                                                           H      Cl     CH 65  156-157                                                                             Ethyl acetate-hexane            21   CH.sub.3 O                                                                           CH.sub.3 O                                                                           Cl     Cl     CH 64  183-184                                                                             Ethyl acetate-hexane            22   CH.sub.3 O                                                                           CH.sub.3 O                                                                           Cl     Cl     N  48  160-161                                                                             Ethyl acetate-hexane            23   (CH.sub.3).sub.2 CHO                                                                 CH.sub.3 O                                                                           CH.sub.3 O                                                                           CH.sub.3 O                                                                           N  58  154-155                                                                             Ethyl acetate-hexane            24   CH.sub.3 O                                                                           (CH.sub.3).sub.2 CHO                                                                 CH.sub.3 O                                                                           CH.sub.3 O                                                                           N  52  --.sup.1)                             25   CH.sub.3 O                                                                           CH.sub.3 O                                                                           (CH.sub.3).sub.2 CHO                                                                 CH.sub.3 O                                                                           N  65  183-185                                                                             Ethyl acetate-hexane            26   CH.sub.3 O                                                                           CH.sub.3 O                                                                           CH.sub.3 O                                                                           (CH.sub.3).sub.2 CHO                                                                 N  75  165-166                                                                             Ethyl acetate-hexane            27   CH.sub.3 O                                                                           CH.sub.3 O                                                                           (CH.sub.3).sub.2 CHO                                                                 (CH.sub.3).sub.2 CHO                                                                 N  50  134-135                               28   CH.sub.3 O                                                                           (CH.sub.3).sub.2 CHO                                                                 (CH.sub.3).sub.2 CHO                                                                 (CH.sub.3).sub.2 CHO                                                                 N  66  Oily                                                                          substance.sup.2)                      __________________________________________________________________________     .sup.1) Amorphous solid. MNR (δ ppm in CDCl.sub.3): 0.87(3H, t,         J=7.2Hz), 1.33(6H, d J=6.0Hz), 3.85(3H, s), 3.93 (2H, q, J=7.2Hz),            3.96(3H, s), 4.02(3H, s), 4.43(1H, m), 5.68(1H, d, J=14.8Hz), 5.77(1H, d,     J=14.8Hz), 6.82-7.01(4H, m), 7.41(1H, s), 7.93(1H, s), 8.27(1H, s)            .sup.2) NMR (δ ppm in CDCl.sub.3): 0.84(3H, t, J=7.2Hz),                1.26-1.45(18H, m), 3.93(2H, q, J=7.2Hz), 4.02(3H, s), 4.21(1H, m),            4.51(1H, m), 4.56(1H, m), 5.73(2H, s), 6.80-6.92(3H, m), 7.01(1H, d,          J=8.2Hz), 7.41(1H, s), 7.93(1H, s), 8.27(1H, s)                          

                                      TABLE 8                                     __________________________________________________________________________     ##STR69##                                                                    Example              Yield                                                                             Melting                                                                             Recrystallization                              No.  A.sup.1                                                                           A.sup.2                                                                           B.sup.1                                                                           B.sup.2                                                                           (%) Point (°C.)                                                                  Solvent                                        __________________________________________________________________________    30   HO  CH.sub.3 O                                                                        CH.sub.3 O                                                                        CH.sub.3 O                                                                        35  165-166.sup.1)                                       31   CH.sub.3 O                                                                        HO  CH.sub.3 O                                                                        CH.sub.3 O                                                                        38  215-216.sup.2)                                       32   CH.sub.3 O                                                                        CH.sub.3 O                                                                        HO  CH.sub.3 O                                                                        62  232-233.sup.                                                                        Dichloromethane- hexane                        __________________________________________________________________________     .sup.1) NMR (δ ppm in CDCl.sub.3): 0.88(3H, t, J=7.2Hz), 3.84(3H,       s), 3.86(3H, s), 3.95(2H, q, J=7.2Hz), 3.97(3H, s), 5.73(2H, s), 6.88-        7.01(5H, m), 7.52(1H, s), 7.94(1H, s), 8.37(1H, s)                            .sup.2) NMR (δ ppm in CDCl.sub.3): 0.86(3H, t, J=7.0Hz), 3.85(3H,       s), 3.94(2H, q, J=7.0Hz), 3.98(3H, s), 4.07(3H, s), 5.73(2H, s), 6.20(1H,     broad), 6.82-6.98(3H, m), 7.08(1H, s), 7.42(1H, s), 7.93(1H, s), 8.27(1H,     s)                                                                       

                                      TABLE 9                                     __________________________________________________________________________     ##STR70##                                                                     No.Example                                                                         R.sup.1, R.sup.2                                                                        ##STR71##                                                                                 ##STR72##                                                                               (%)Yield                                                                          Point (°C.)Melting                                                           Recrystallization             __________________________________________________________________________                                                   Solvent                        55   6-Cl, H                                                                                  ##STR73##                                                                                 ##STR74##                                                                              34  112-114                                                                             Ethanol                        56   6-CH.sub.3, H                                                                            ##STR75##                                                                                 ##STR76##                                                                              30  121-123                                                                             Ethanol                        57   6-(CH.sub.3).sub.2                                                                       ##STR77##                                                                                 ##STR78##                                                                              40  133-135                                                                             Ethanol                        58   6,7-(CH.sub.3 O).sub.2                                                                   ##STR79##                                                                                 ##STR80##                                                                              57  143-144                                                                             Ethanol                        59   6,7-(CH.sub.3 O).sub.2                                                                   ##STR81##                                                                                 ##STR82##                                                                              43  139-141                                                                             Ethyl acetate-hexane           60   6,7-(OCH.sub.2 CH.sub.2 O)                                                               ##STR83##                                                                                 ##STR84##                                                                              68  154-156                                                                             Ethanol                        61   6,7-(CH.sub.3 O).sub.2                                                                   ##STR85##                                                                                 ##STR86##                                                                              70  143-144                                                                             Ethanol-hexane                 62   6,7-(CH.sub.3 O).sub.2                                                                   ##STR87##                                                                                 ##STR88##                                                                              75  160-161                                                                             Dichloromethane-isopropylet                                                   her                            __________________________________________________________________________

What is claimed is:
 1. A compound represented by the general formula:##STR89## wherein Y represents a nitrogen atom or C--G, wherein Grepresents a carboxyl group which may be esterified; ring R is anitrogen-containing unsaturated heterocyclic group which may besubstituted or unsubstituted; each of rings A and B may have asubstituent; n represents an integer from 1 to 4; and k represents theinteger 0 or 1, or a salt thereof.
 2. The compound of claim 1, whereinsaid nitrogen-containing unsaturated heterocyclic group is a 5-memberedring, or a salt thereof.
 3. The compound of claim 1, wherein saidnitrogen-containing unsaturated heterocyclic group contains 1 to 4nitrogen atoms as ring component atoms, or a salt thereof.
 4. Thecompound of claim 1, wherein said nitrogen containing unsaturatedheterocyclic group is imidazol-1-yl, pyrazol-1-yl, 1,2,4-triazol-1-yl,1,2,4-triazol-4-yl, 1,2,3-triazol-1-yl, pyrrol-1-yl or tetrazol-1-yl, ora salt thereof.
 5. The compound of claim 1, wherein said n is 1, or asalt thereof.
 6. The compound of claim 1, wherein said Y is C--G and Gis a C₁₋₆ alkyloxycarbonyl group, or a salt thereof.
 7. The compound ofclaim 1, wherein said G is an ethoxycarbonyl group, or a salt thereof.8. The compound of claim 1, wherein each of A ring and B ring mayindependently be substituted with the same or different 1 to 4substituents selected from the group consisting of a halogen atom,nitro, optionally substituted alkyl, optionally substituted hydroxyl,optionally substituted thiol, optionally substituted amino, optionallysubstituted acyl, optionally esterified carboxyl and an optionallysubstituted aromatic cyclic group, and the adjacent substituents may belinked together to form the group of the formula: --(CH₂)_(m) -- or--O--(CH₂)_(l) --O-- wherein m is an integer of 3 to 5 and l is aninteger of 1 to 3 which forms a ring, or a salt thereof.
 9. The compoundof claim 8, wherein said optionally substituted hydroxyl group ismethoxy group, or a salt thereof.
 10. The compound of claim 8 whereinsaid optionally substituted hydroxyl group an unsubstituted hydroxylgroup, or a salt thereof.
 11. The compound of claim 1, wherein thesubstituent of the ring A is a methoxy group at the 6- or 7- position ofthe quinoline ring, or a salt thereof.
 12. The compound of claim 1,wherein the substituent of the ring B is a methoxy group at the 3- or4-position of the benzene ring, or a salt thereof.
 13. The compound ofclaim 1 which is selected from the group consistingof:6,7-dimethoxy-4-(3,4-dimethoxyphenyl)-2-(1,2,4-triazol-1-ylmethyl)quinoline-3-carboxylicacid ethyl ester,6,7-dimethoxy-4-(3-isopropoxy-4-methoxyphenyl)-2-(1,2,4-triazol-1-ylmethyl)quinoline-3-carboxylicacid ethyl ester,6,7-dimethoxy-4-(4-hydroxy-3-methoxyphenyl)-2-(1,2,4-triazol-1-ylmethyl)quinoline-3-carboxylicacid ethyl ester,6,7-dimethoxy-4-(3,4-dimethoxyphenyl)-2-(2-ethylimidazol-1-ylmethyl)quinoline-3-carboxylicacid ethyl ester,6,7-dimethoxy-4-(3,4-dimethoxyphenyl)-2-(pyrazol-1-ylmethyl)quinoline-3-carboxylic acid ethyl ester,6,7-dimethoxy-4-(4-methoxyphenyl)-2-(1,2,4-triazol-1-ylmethyl)quinoline-3-carboxylicacid ethyl ester,6,7-dimethoxy-4-(4-isopropoxy-3-methoxyphenyl)-2-(1,2,4-triazol-1-ylmethyl)quinoline-3-carboxylicacid ethyl ester, or a salt thereof.
 14. An anti-inflammatory agentcontaining a compound represented by the general formula: ##STR90##wherein Y represents a nitrogen atom or C--G, wherein G represents acarboxyl group which may be esterified; ring R is a nitrogen-containingunsaturated heterocyclic group which may be substituted orunsubstituted; each of rings A and B may have a substituent; nrepresents an integer from 1 to 4; and k represents the integer 0 or 1,or a salt thereof, along with a pharmaceutically acceptable carrier. 15.An anti-pyretic analgesic agent containing a compound represented by thegeneral formula: ##STR91## wherein Y represents a nitrogen atom or C--G,wherein G represents a carboxyl group which may be esterified; ring R isa nitrogen-containing unsaturated heterocyclic group which may besubstituted or unsubstituted; each of rings A and B may have asubstituent; n represents an integer from 1 to 4; and k represents theinteger 0 or 1, or a salt thereof, along with a pharmaceuticallyacceptable carrier.
 16. An anti-arthritic agent containing a compoundrepresented by the general formula: ##STR92## wherein Y represents anitrogen atom or C--G, wherein G represents a carboxyl group which maybe esterified; ring R is a nitrogen-containing unsaturated heterocyclicgroup which may be substituted or unsubstituted; each of rings A and Bmay have a substituent; n represents an integer from 1 to 4; and krepresents the integer 0 or 1, or a salt thereof, along with apharmaceutically acceptable carrier.
 17. A method for the prophylaxis ortreatment of inflammation in a mammal comprising administering ananti-inflammatory effective amount of an agent according to claim 14 toa mammal in need thereof.
 18. A method for promoting antipyreticanalgesic action in a mammal comprising administering an antipyreticanalgesic effective amount of an agent according to claim 15 to a mammalin need thereof.
 19. A method for the prophylaxis or treatment ofarthritis in a mammal comprising administering an antiarthriticeffective amount of an agent according to claim 16 to a mammal in needthereof.